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The Male Pill: When Is It Coming? Public Transcript
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Hi I’m Michelle Dang filling in for Wendy Zukerman this week. She has a tummy ache from eating too much vegemite. And you’re listening to Science Vs from Gimlet. Today on the show – we’re pitting facts against fending off fertilization.

We are taking on the Male pill. This is a topic you’ve all been asking for and it’s been making headlines for years now... We found tons of news stories that said male birth control is just around the corner…

MEDIA CLIPS:

<<The responsibility of taking a daily birth control pill has fallen squarely on the shoulders of women, but that may soon be changing>>

<<Scientists have announced that they’ve developed a male contraceptive pill that’s been showing impressive results in lab mice>>

<<Researchers have spent decades researching a new birth control for men. According to a new study they may finally be making headway >>

Seems like we’ve been oh so close to having this “male pill” for years now with a big fat nothing to show for it. Is this a big tease or are we really on the edge of a breakthrough? 

Because now the stakes seem higher than ever in the U.S… The Supreme Court overturned Roe v Wade[1], which has got a lot of people thinking oh, crap - what do we do now ...[2]

MEDIA CLIPS:

<<A lot of people in this country have also been looking up options when it comes to contraception and reproductive health care>>

<<With Roe v Wade out, women will be asking more of men in the family planning department>>

Now, even before Roe v Wade was overturned, it seemed Iike we could use more options here for spermers. Especially when you realize just how many pregnancies in the US are whoops! A surprise. One big study looking at national data, found that in 2011, 45% of pregnancies were unplanned – yeah, almost half.[3][4] So today on the show, we’re going to find out … where the heck is the male pill? Will we ever get there?

Because when it comes to the male pill … there’s a lot of

<< they may finally be making headway  >>

And then there’s science.

AHHH

Coming after the break

PRE ROLL

Welcome back. Today we’re looking at male birth control.

Just a note – we’re using the terms male and female birth control – because that’s how a lot of the research talks about it. And a lot of the research is in, cisgender people. But we’re going to use inclusive language where we can.

So people who make sperm basically have just two forms of decent birth control in their ballpark … condoms and vasectomies. We know condoms are great, they’re very handy against STDs.[5] And they’re very effective in preventing pregnancy. But only if they’re used perfectly … in the real world, they fail 13% of the time.[6][7] 

Vasectomies aren’t cutting it either … I mean OK, they are, technically cutting it[8][9] … The surgeries are very effective[10]. But that requires going under the knife… and if you change your mind and want to reverse it… it doesn’t always work.[11] So, overall you have to be pretty sure you want to hop off the fertility train.[12] 

And even though the female pill has its downsides, there’s one great thing about it– you get your fertility back if you just stop taking it. So we want the same thing for spermers. A male Pill. Why don’t we have it?

Well, to answer this, one of the first things I had to figure out was. How are babies made? Just kidding. I may sound like I’m twelve, but we can skip that part but really. Is it that hard to figure out how to stop sperm in their tracks?

JA: For sure. And you might say why?

This is John Amory[13], he’s a professor of internal medicine from the University of Washington, he specializes in male reproductive health.

JA: And I'd say because the physiology of men and women is so different. So women, when they go through puberty, they make an egg every month unless they're pregnant and because then they turn off egg production.

Yeah, when you get knocked up, your body ramps up certain hormones, like progesterone, and basically hangs up a “Sorry, we’re closed.” sign[14]. So the ovaries know to stop sending out eggs. And part of what the female birth control pill does is mimic this process, by ramping up these same hormones. And that stops the egg in the same way.

Take the pill away, and voila. All systems are a go. And we’ve known this for ages … Scientists first saw it way back in the 1930s, when they were pumping hormones into animals[15][16].… and by the late 50s - scientists had figured out the female pill.[17] And today there’s lots of options that are effective … implants, injections, IUDs, patches, rings.[18][19] 

So that egg-stopping process is pretty straightforward because we can mimic what happens during pregnancy. But when it comes to sperm - there’s no stop sign

JA: Men start making sperm when they hit puberty[20], and they do so until they die[21]. And there's nothing for us to mimic. So, yes, I think physiologically it's easier to make a female than a male contraceptive.

WHY IS IT HARD - SPERMAPALOOZA

Yeah, for sperm… they may look cute and innocent, but put them all together and they’re a beast to tackle here. And a big reason why - is that they’ve got strength in numbers.

JA: You know, men make a lot of sperm. Men make about 1000 sperm every second or every heartbeat[22]. 

Yeah basically the biggest challenge for male birth control, is that we need to stop a big butt load of sperm. Big ball load?

The amount of sperm in a single ball load is nuts  – a healthy man puts out around 15 to 200 million sperm per milliliter of semen…  per milliliter!![23] That’s like just 1/5th of a teaspoon.[24] And that's not even a full load ... generally when a dude comes …

JA: Total sperm, you have around 30 to 300 million per ejaculate.  

Like what?? That is insane to me. When I picture this, I think of that scene in Lord of the Rings…. Where there’s a sea of orcs, continuing to be born by the second. Basically that, but multiplied thousands of times over. Yeah. THAT IS A LOT OF SPERM!!! in just a spoonful of splooge.

So when it comes to birth control. We need to cut that horde way down.  But good news is … we don’t have to go totally John Wick and kill all the sperm. To stop pregnancies, the target is to bring that sperm concentration from more than 15 million down to one million sperm per milliliter. [25]

And the wild thing is, we almost had something that could do this DECADEs ago.

It was back around the 50s … there was this drug called WIN 18466 being developed by a pharma company called Sterling Winthrop.[26]

And the way they came across it as birth control was pretty much by accident. They were developing it to fight off parasites, amoeba infections – and they were testing this in rats.[27][28] 

That is, until they noticed something weird. Usually, it’s not hard to get rats to have babies… they can pop out a litter of pups every few weeks.[29] But the male rats getting treated with this drug … they weren’t making any babies.

JA: Couldn't get any pregnancies. So they looked at the testis and there's no sperm and they're like, Holy cow!

They also noticed that when they stopped the drug, the rats were fertile again. It was fully reversible. And it seemed like the rats were fine, no side effects.[30] The scientists thought, ‘Hey this might be a birth control breakthrough, would this work in humans?’

So they decided to do something that - today - seems pretty sketchy.[31] They organized an experiment at a prison.[32] It was at Oregon State Penitentiary, starting in the late 1950s. They got 60 men who were prisoners, gave them the drug, and watched what happened with their sperm. 

About a year in - everything was going pretty darn well.[33][34][35] 

JA: Looked great. All of them had their sperm counts go down. Stop the drugs. Sperm count. Come back up. Everybody's happy. They seem fine.

Their sperm counts plummeted. They were infertile, just like the rats! A scientist’s dream… but it didn’t last too long…

JA: And then they discovered the unanticipated side effect

John’s mentor was one of the people researching this drug. And he told John - that one guy in the study started getting really sick. Sweating… vomiting … nausea. At first, they weren’t sure why this guy was so sick - when the other people taking the drug were fine.

They examined the guy…and they said…you know what? It seems like he has alcohol poisoning.[36] But he wasn’t supposed to be drinking… he was in prison… and so they asked him have you been drinking cleaning fluid or something?

JA: It turned out that somebody had smuggled the guy in a bottle of Jim Beam or Jack Daniels or something. So he pulls this out of his coat and shows it to the investigators and says, no, it wasn't cleaning fluid. It was this.

MD: haha

JA: And that's when they knew they had a problem.[37] 

Here’s what was going on: The drug messed with the body’s production of sperm, by disabling an enzyme in the balls. BUT this same enzyme also breaks down alcohol in the liver.[38] Meaning, the enzyme wasn’t working right, so the alcohol stuck around and acted like a toxin … leading to those nasty side effects.[39][40] 

So if you were on this drug for birth control, you’d have to give up alcohol. They knew this would be a hard sell… so - they halted the trial and gave up on this drug as a male contraceptive.

Scientists, like John, are actually poking around this enzyme again - but no luck yet.[41] And yeah in the past 60 years… there’s been a lot of other stuff tested… but basically everything - has had performance issues. And no male pill has made it to the market.

It’s hard to say exactly why, but John told us that part of it might be that we got the female pill first. Right around the time of that prison experiment, female birth control was approved![42] The first contraceptive pill became available in the US in the late ‘50s. And then the floodgates basically opened.[43] Within five years, it was a major player in the US birth control scene; millions of women were taking it.[44] So it’s possible that this slowed down research into the stuff for sperm.

We don’t know for sure, but it does look like female birth control tends to get more money. For example, one database found that in 2018, female birth control R&D got 5 times as much in funding than male birth control.[45]

 

Still, research on the male pill has been dribbling out - and it DOES seem like we’re getting closer. After the break … we'll look at the most promising drug yet to try to stop the orc army of sperm.

BREAK

HORMONAL

Welcome back. So we had one early dead end for male birth control. And since then, we haven't been able to crack this nut of a problem. But it turns out, there IS a drug that has kept the ball rolling …and it’s really starting to pick up speed.

For this I talk to Brian Nguyen – he’s an OBGYN from the University of Southern California who also specializes in family planning and male contraceptives.

BN: And as a male OBGYN provider, it always struck a chord with me that men should be doing something as well, or men should be sharing that responsibility. And so that's what made me think to myself, Well, I need to do something about this.

Before we jump into how this one works. We need to know that there's a very important ingredient for making sperm. A fancy dancy hormone you may have heard of *dun dun drumroll* testosterone.[46]

The balls make testosterone. A LOT OF IT. They send a little bit of the stuff around the body to make and do male body things. But the balls keep most of it. In fact, the concentration of testosterone in the balls can be up to 125 times greater than in the rest of the body.[47] And they need all that ball testosterone, to be the un-ball-lievable sperm factory that they are.

The brains behind this operation is… the brain. Your brain keeps track of how much testosterone is in your body. And it does that by looking at how much of it is in your blood. And based on that, it tells your balls how much testosterone to make ... If there’s too little, the brain sends signals to the balls to make more. And if there’s too much, the brain says stop.  [48] 

Scientists have figured out - they can take advantage of this. They can trick the brain by adding more testosterone to the body - in the form of a drug. The brain starts thinking. ‘WHOA! BALLS you are making waaay too much testosterone ... Please tone it down a bit.’

BN: And the testicles would stop making testosterone, which in that same process would stop making sperm. So pretty. Pretty easy, right?

Yeah, seems easy, and we've known about this for decades. But it’s actually been pretty hard to pull off. When we started getting clinical trials on testosterone for birth control, researchers saw that it didn’t work across the board. Like, not everyone’s sperm counts went down enough to be infertile.[49]

So scientists knew they had to do better. And after tinkering around in rats,[50][51] they realized they could use a different hormone to suppress the sperm factory even more: progestin. This is what you find in female birth control[52][53]

And turns out - progestin works really well for shutting down sperm production.[54]  Together with testosterone – the combo drops sperm counts lower and faster …  than testosterone on its own.[55][56] 

And today, there’s a progestin/testosterone drug in the works it's called Nes/T. Brian’s actually part of a large team running clinical trials on it around the world … By the way, it’s not a pill…  

BN: Producing a male pill has always been very challenging, because at dose you need it can actually be toxic to the liver. So for that reason we’ve not been able to develop a male pill

So this one Brian’s working with? It comes in the form of a gel that men rub onto their shoulders.

MD: Oh, is it, so is it like a lotion?

BN: Yeah, it's kind of like I mean, it's alcohol based, right? So it's kind of like hand sanitizer in that sense.

MD: How often do they have to apply it?

BN: You know, daily. On their shoulders on both sides. And they kind of rub it in.

Weird right? It goes through the skin! And into the bloodstream. And Brian’s pretty excited about it. It’s been checked for safety, and now they’re looking at how well it works. The team is testing it in hundreds of couples around the world right now.[57] 

They give them the gel, drop their sperm counts down … then tell the couples to stop any other form of birth control – and just use this. They check their sperm counts at the clinic once a month … restock ’em on gel. And see if any of these couples get pregnant over the course of a year with their regular hanky panky.[58] 

MD: Do do we know how effective it is yet?

BN: Nothing I can say on record. But what I can tell you so far is that the preliminary results of the trial have been promising in a way that we're currently planning for phase three

MD: And this is the furthest along that a male birth control has come?

BN: Correct.

Yeah this is the furthest – a male contraceptive like this has come in the US.[59] So - Brian mentioned phase three – that’s the next trial they’ll need to do. Another bigger one, testing the drug in thousands of people to see how well it works. And that process could take years.[60][61] But you know, already – one of the top nerds from the agency funding this study says the gel stacks up well compared to what we’ve got for women. She said, quote “The efficacy rate appears better than the pilland, so far, seems on par with long-acting reversible contraceptives for women.”[62] 

BN: It's super exciting. We're all, you know, very enthusiastic about it. I think the hard part is that, you know, as scientists, we are always, you know, prepping for the worst-case scenarios. And so we always try to stay measured. But by saying that I'm excited, you should take that to a different level.

So this stuff - it’s sounding pretty promising. It’s probably what’s most likely to reach the market before other contenders. But it could still be 10 years away.[63] And there is a caveat here … these drugs will probably have side effects.[64]

Brian said his team has tweaked the dosing to try to minimize them[65] - but still, these are a thing when it comes to hormonal drugs.

BN: I mean, any hormones can have side effects. … You know, some changes to their mood, skin changes like acne

These drugs can also lead to weight changes[66]. All of which probably sounds familiar to anyone who has taken female hormonal birth control.[67] The side effects for testosterone-based drugs can actually be pretty similar.[68] And they raise the question - of whether men will want to take this stuff.[69] Producer Meryl Horn asked Brian about it …

MH: Overall, do you think men want this?

BN: Absolutely. What's you know, what's interesting is that we never really ask women the same question of do you want a female contraceptive? We just assume that they do, right?

MH: Yeah.

When scientists survey the people in clinical trials for male birth control - they generally find that, despite any side effects, at least half of them say they were happy with the drug[70][71][72][73][74].  

But another kinda complicated piece is that the calculus for women and men is different. If you’ve got a uterus and the associated bits, you’re balancing side effects of birth control against the risks of pregnancy. And pregnancy is pretty much always the riskier option.[75] But when it comes to male birth control … if you can’t get pregnant? You may be less willing to take on some crappy side effects.[76]

All this is a big reason why scientists are working on other options too.[77] And there are things in the works - drugs that don't use hormones,[78] even physical blockers like a gel to stop sperm from coming out of the testicles[79] ... some of this are still in animal trials, and there are a few that have made it to testing in people.[80] So it's worth keeping an eye on that too.

BN: So in the ideal world, we would have lots of options for both men and women, in the same way we have more than 12 options currently that people with with uteruses can choose from, I think it’s important to have that many or more for male partners

OK, so where does this leave us? Well, it turns out the road to getting a male birth control has been bumpy for all sorts of reasons.  Dealing with endless amounts of sperm is just harder than dealing with one egg at a time… And there’s been a bunch of fits and starts, where scientists got excited - but things ended up going flaccid. Because of weird side effects, or drugs not working well enough … overall, it doesn’t seem to have gotten as much money or attention as the stuff for people with uteruses.

Still, Brian thinks we might be at an inflection point ... with his trial getting further and further, and because of how the Supreme Court decision is changing the conversation...

BN: With the overturning of Roe versus Wade, seeing my inbox, you know, kind of bubble up with messages from men saying that they want to join male kinds of clinical trials because they feel threatened by the recent Dobbs decision has been very encouraging  it does hearten me to know that there are men out there who saw this as a  threat and a call to action

That’s Science Vs.

CITATIONS

CREDITS reminders

This episode was produced by me, Michelle Dang, with help from Disha Bhagat, Rose Rimler and Meryl Horn. We’re edited by Blythe Terrell. Additional editing help on this episode from Caitlin Kenney and Jorge Just. Wendy Zukerman is our Executive Producer. Fact checking by Diane Kelly. Mix and sound design by Bumi Hidaka. Music written by Bumi Hidaka, Emma Munger, Bobby Lord, and Peter Leonard. Special thanks to Thomas Rossetti, Jacob Rimler, Jack Weinstein. We got the term spermers from Mona Chalabi - she’s got a great podcast called Am I Normal? - check it out.


[1] https://www.supremecourt.gov/opinions/21pdf/19-1392_6j37.pdf

[2] “Birth control restrictions could follow abortion bans, experts say”  June 2022 NBC

As states ban abortion, demand for birth control and abortion pills is rising.” June 2022 NYT

New Research Shows State Restrictions Reduce Contraception Use” Sept 2022 Pewtrusts

[3] NEJM 2016 In 2011, a total of 6.1 million pregnancies occurred in the United States (Table 1); 45% of these pregnancies (2.8 million) were unintended, as compared with 51% of the pregnancies in 2008

[4] 2022 UN report that shows similar numbers of "nearly half of all pregnancies are unintended"

[5]​​ Condom effectiveness for STD and HIV prevention has been demonstrated by both laboratory and epidemiologic studies. Evidence of condom effectiveness is also based on theoretical and empirical data regarding the transmission of different STDs, the physical properties of condoms, and the anatomic coverage or protection provided by condoms.

[6] Long-acting reversible contraceptives (the IUD and the implant) had the lowest failure rates of all methods (1%), while condoms and withdrawal carried the highest probabilities of failure (13% and 20%, respectively).

[7] Male condoms and internal (female) condoms are considered “coitally dependent” methods, because they are generally employed near the time of sexual intercourse. The male condom has a typical-use failure rate of 13%, and a perfect-use failure rate of 2%.

[8] https://www.plannedparenthood.org/learn/birth-control/vasectomy

[9] The two most common surgical techniques for accessing the vas during vasectomy are the traditional incisional method and the no-scalpel vasectomy (NSV) technique. The conventional incisional technique involves the use of a scalpel to make one or two incisions and the NSV technique uses a sharp, forceps-like instrument to puncture the skin, the latter approach aimed to reduce adverse events (e.g., bleeding, infection, and pain).

[10] Vasectomy is one of the most effective forms of birth control. In the first year after a man has a vasectomy, a few couples will still get pregnant. But the number is far lower than the rates of pregnancy among couples using condoms or oral contraceptive pills.

[11] Descriptive analysis showed higher post-operative patency (80.5% vs 91.4%) and pregnancy rates (47.7% vs 73.3%) after microscopic vasovasostomy. (compared with macrosurgical techniques)

[12]  Although patients should be counseled to consider vasectomy a permanent means of contraception, close to 20% of men express a desire for children after the procedure (3). For men who want to achieve natural conception after vasectomy, vasectomy reversal (VR) represents the only option. Approximately 2–6% of American men will ultimately undergo reversal (1,3).

[13] https://gim.uw.edu/faculty/john-amory-md-mph-msc

[14] Jones and Lopez  Human Reproductive Biology  2014 p 247: Ovulation does not normally occur during the luteal phase of the female cycle nor when a woman is pregnant. During these times, high levels of progesterone (as well as moderate levels of estrogens) exert negative feedback on the hypothalamus and pituitary…Follicular growth slows down because of a reduction in FSH, and suppression of LH inhibits ovulation.

[15] Animal experiments in the late 1930s demonstrated that high-dose progesterone could arrest ovulation. Chemist Dr Carl Djerassi synthesized progestin from an extract of Mexican wild yam root in the late 1940s, and the concept of arresting ovulation in women became reality.

[16] 1936: From these results it is clear that post-coital ovulation in the oestrous rabbit is prevented by the daily injection of corpus luteum preparations [ed note: corpus luteum is source of progesterone] in amounts equal to, or greater than, the quantity necessary to sustain pregnancy in the castrate rabbit.

[17] The first hormonal pill was called Enovid. It was approved by the Federal Drug Administration (FDA) in 1957 as treatment of menstrual disorders. Its capacity to regulate birth was only recognized several years later and it was not until 1959 that the pharmaceutical company Searle applied to the FDA for approval of a pill that would be marketed as a contraceptive. In June 1960, approval was granted … In the first clinical studies, Enovid’s contraceptive efficacy was excellent; reaching 100% but this drug induced many side effects.

[18] CDC Contraception page - Typical use failure rate for implants(0.1%), injections(4%), IUDs(<1%), patches (7%), rings (7%)

[19] See figure 1 https://www.contraceptionjournal.org/article/S0010-7824(11)00049-7/fulltext

[20] Spermarche occurred at a median age of 13.4 yr (range, 11.7-15.3 yr), at a time when testicular size was 4.7-19.6 ml (median, 11.5 ml), and pubic hair distribution was 1-5 (median, 2.5).

[21] men do not experience a major, rapid (over several months) change in fertility as they age (like menopause).

[22]One study that utilized homogenization-resistant spermatids as the standard determined that human daily sperm production (dsp) was at 45 million per day per testis. For each human that means ∼1,000 sperm are produced per second.

[23] Normal sperm densities range from 15 million to greater than 200 million sperm per milliliter of semen.

[24] 1 mL = 0.20 tsp [https://www.unitconverters.net/volume/ml-to-teaspoon.htm]

[25]  A second study extended this to ask ‘how low does a sperm count need to go?’, and used 3 million/mL as the cut-off for entry to the efficacy phase. This increased the response rate (92% of men achieved sperm counts below this threshold and entered the efficacy phase), and again excellent efficacy was demonstrated with a Pearl Index of 1.4 (95% CI 0.4 to 3.7).5 Although a Pearl Index of 8.1 (95% CI 2.2 to 20.7) was achieved even in men who were not azoospermic, it was subsequently decided that <1 million/mL was the appropriate sperm count cut-off for future contraceptive efficacy studies.

[26] WIN 18,446 is a bis-(dichloroacetyl)-diamine which inhibits aldehyde dehydrogenase 1a2, (IC50 = 300 nM), a testes-specific isoform of the enzyme involved in vitamin A metabolism. In this way, WIN 18,446 suppresses the expression of several genes that are regulated by retinoic acid and are necessary for spermatogenesis. As a result, WIN 18,446 may cause infertility in males.

[27] Drobeck 1962 Surrey and Mayer (1961a,b) recently reported the synthesis of a new series of compounds, the bis (dichloroacetyl) diamines, various members of which have potent amebacidal activity. Coulston et al. (1960) and Beyler et al. (1961) observed that three of these compounds, Win 13,099, Win 18,446, and Win 17,416, affected the germinal epithelium and were specific antispermatogenic drugs in rats, monkeys, and dogs. Heller et al. (1961) also reported successful suppression of spermatogenesis in man with these drugs.

[28] Deitrich 1963 It has been reported that certain bis-dichloroacetylamines are capable of inhibiting spermatogenesis in laboratory animals (16)) and related compounds have considerable promise as antiamebic agents (17). One side effect of these compounds has been a reaction to ethanol in man and animals.3

[29] Male rats reach sexual maturity at about 6 to 10 weeks of age; females reach maturity at 8 to 12 weeks. From this age onward, females and males should be housed separately. The average gestation time is 21 to 23 days …The usual litter size is 8 to 18 pups.

[30] Coulston 1960   Summary: These compounds proved to be relatively nontoxic substances which exert a specific effect upon the testes of the species studied. 2. This biologic effect on the testes is characterized by arrest of spermatogenesis which is completely reversible within a few weeks after withdrawal of the drug. The Leydig, SertoIi, and spermatogonial cells appear to be normal even under the full influence of these drugs.

[31] Until the early 1970s, a wide variety of pharmaceutical research was conducted on prisoners, and by 1972, “more than 90% of investigational drug toxicity testing was conducted on prisoners.” In the 1950s through the 1970s, biomedical experiments were conducted at Holmesburg Prison in Philadelphia, and some resulting in permanent injuries. Specifically in light of this history, regulations were adopted to protect human subjects and particularly vulnerable populations, including prisoners. U.S. regulations limit studies involving prisoners to those that examine conditions causing incarceration or that specifically affect prisoners as a group. There is a general prohibition on studies that are meant to solely benefit the general U.S. population. 

[32] Heller 1961     Win 18,446 was found by Beyler and Potts (1959) [Reference says personal communication - Beyler is second author on Coulston 1960 paper] to be four to eight times more potent in antispermatogenic activity in rats than Win 13,099. It was administered to nine inmates in amounts of 125 or 250 mg, twice daily.

[33] Heller 1961     For the remaining five volunteers, control sperm count averages were 132, 206, 71, 97, and 59 million/cc. Each of these dropped to counts of 0 to 4 million/cc within 8-11 weeks. … The only symptomatic effect reported by those taking Win 18,446 was “gas.” This included attending complaints of “rumbling,” “growling,” “bloating,” and “gas pains,” by six of the nine inmates.

[34] Heller 1963 Histopathology of the Human Testes as Affected by bis(dichloroacetyl)diamines == PMID: 14089658

[35] Roth & Amory 2016   More than 50 years ago, the oral administration of WIN 18,446 was shown to reversibly inhibit spermatogenesis in many species including man after 12 weeks of administration.83–85 Testicular biopsies from men in these studies treated with WIN 18,446 revealed a complete arrest of spermatogenesis, with only spermatogonia remaining in the seminiferous tubules.84 It was apparent that these compounds had no effect on the endocrine function of the testes, but their mechanism of action was undetermined. Nevertheless, at least 60 men were administered WIN 18,446 for up to 1 year with sperm concentrations below 1 million/mL of ejaculate,83 and no significant adverse events. Unfortunately, further development was abandoned in the 1960s, as subjects taking WIN 18,446 experienced disulfiram reactions with nausea, vomiting, and sweating, when they drank alcohol.

[36] Alcohol poisoning signs and symptoms include: Confusion, Vomiting, Seizures, Slow breathing (less than eight breaths a minute), Irregular breathing (a gap of more than 10 seconds between breaths), Blue-tinged skin or pale skin, Low body temperature (hypothermia), Passing out (unconsciousness) and can't be awakened

[37] A group of 60 state prisoners volunteered to participate in studies involving both semen analyses and testicular biopsies. MacLeod obtained complete inhibition of spermatogenesis and found that the profound effects were completely reversible within several months. This raised the hopes of scientists working in the area of population control that this drug would prove to be an effective birth control pill for men, but such hopes were dashed when it was found that nonprisoners became severely ill if they drank alcoholic beverages (ie, an Antibus-like effect).

[38] WIN 18,446 reversibly suppresses spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2, and identifies ALDH1a2 as a promising target for the development of novel, nonhormonal male contraceptives. Furthermore, this finding raises the possibility that a defect in the biosynthetic pathway of retinoic acid could underlie some causes of male infertility.

[39] Alcohol is primarily metabolized by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The metabolism of alcohol produces acetaldehyde, acetate, and reactive oxygen species. Both high ADH activity and low ALDH activity cause an excess of acetaldehyde and result in oxidative stress (Ohta et al., 2004).

[40] A clinical study of a bisdichloroacetyldiamine analog in the RA pathway, WIN18,446, was used to treat over 60 men for 1 year (39). The drug was well tolerated and efficacious at inhibition of spermatogenesis. However, development of the drug was halted after finding that consumption of alcohol with the drug induced a severe disulfiram reaction, due to off-target inhibition of a liver enzyme, aldehyde dehydrogenase (ALDH)-2, which detoxifies aldehyde during alcohol metabolism.

[41] A different aldehyde dehydrogenase subfamily, ALDH1A, is involved in synthesis of RA and a testis-specific member includes ALDH1A2. Covalent and noncovalent small molecule inhibitors of ALDH1A2 recently have been developed. Ternary x-ray cocrystal structures of the inhibitors provide the structural framework for design of potent, selective inhibitors of ALDH1A2 (40).

[Interview w/JA + 2012 interview here: https://www.science.org/doi/10.1126/science.338.6105.318]

[42] On 23 June 2000 the United States celebrated the fortieth anniversary of the approval of Enovid, the first oral contraceptive. (FDA approval 6/23/1960

[43] Ortho-Novum received FDA approval for their contraceptive pill in 1962

[44] In 1965, five years after the Pill was approved, 27% of American women reported use of the Pill,

1963 - 2.3 million American women are using the Pill.

[45] G-FINDER 2020 Report Nearly three-quarters ($46m, 71%) of all reported funding for contraception R&D in 2018 was directed to the development of products intended for female end-users1

, reflecting a research agenda historically and still largely dominated by products for women and girls. Remaining funding was balanced between products intended for male end-users ($9.2m, 14%) – a growing field of study into novel contraceptive options beyond currently available condoms and vasectomy – and products without a clear or specified intended user ($9.0m, 14%). More than three-quarters of all funding for male contraceptive R&D was provided by the US NIH ($7.1m, 77%) – far outstripping all other funders – almost half ($3.4m) of which went to the University of Minnesota for R&D into novel targets for male contraception.

[46] Testosterone (T) is the androgen in the testis that is required for initiating and maintaining spermatogenesis, and the production of mature sperm is intimately dependent on androgen action within the testis. Therefore, in the scenario of an absence of T, or its receptor, spermatogenesis does not proceed beyond the meiosis stage and results in male infertility.

[47] Testosterone is produced by Leydig cells in the interstitial space of the testis. As a result of the local production, testosterone levels in the testis in men are 25 to 125-fold greater in the testis (340 to 2,000 nM) as compared to serum (8.7–35 nM).

[48] A negative feedback system occurs in the male with rising levels of testosterone acting on the hypothalamus and anterior pituitary to inhibit the release of GnRH, FSH, and LH. The Sertoli cells produce the hormone inhibin, which is released into the blood when the sperm count is too high. This inhibits the release of GnRH and FSH, which will cause spermatogenesis to slow down. (Ed note: [LH secretion induces the testes to make testosterone, so less LH means less testosterone. Eventually, less testosterone]

[49] https://pubmed.ncbi.nlm.nih.gov/20933120/

[50] https://onlinelibrary.wiley.com/doi/full/10.1002/j.1939-4640.2003.tb02695.x

[51] https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/1j92gb455

[52] IUDs, implants, injection, pills, patches, and rings all contain/release progestin. [CDC contraception webpage]

[53] https://www.kff.org/womens-health-policy/fact-sheet/oral-contraceptive-pills/

[54] In the hopes of achieving 100% azoospermia in men on hormonal contraceptive trials, more recent male contraceptive studies have combined progestins with testosterone. Progestins additively suppress FSH and LH secretion from the pituitary

[55] Progestin coadministration increased both the rate and extent of suppression. Caucasian men suppressed sperm output faster initially but ultimately to a less complete extent than did non-Caucasians. … Male hormonal contraceptives can be practically applied to a wide range of men but require coadministration of an androgen with a second agent (i.e. progestin) for earlier and more complete suppression of sperm output.

[56] The addition of progesterone derivatives (called progestins or progestagens) to testosterone increases

the rates of spermatogenesis inhibition by further inhibiting pituitary production of gonadotropins and

possibly acting directly on germ cells.32 Progestins alone may be sufficient for inhibiting spermatogenesis; however, without exogenous testosterone, a hypogonadal state would be induced with its resultant undesirable side effects. Together, progestins and testosterone have synergistic effects, affording a lower dose of testosterone to achieve sufficient suppression of spermatogenesis and achieve it in a shorter time than testosterone alone

The addition of a progestin to exogenous androgens augments central feedback inhibition, more profoundly and rapidly inhibiting FSH and LH release (19), and may also have direct inhibitory testicular effects (20).

[57] https://clinicaltrials.gov/ct2/show/NCT03452111

[58]Contraceptive phase: 12 months ; Efficacy Phase: After sperm concentration is reduced to the desired level, participants will enter the efficacy phase. During this period, participants will continue to apply the gel so that sperm concentrations are maintained at a level of 1 million/mL or less. Couples will stop using other forms of contraception and will only depend on the gel for pregnancy prevention. Participants are expected to come to the site every month during this phase to obtain the gel, screen for side effects, provide blood for labs, and to confirm continued suppression of sperm production.

[59] This is the first phase IIb efficacy study of a self-administered, single-product male hormonal contraceptive

No male birth control product has made it to Phase III in the United States,” said Dr. Blithe.

[60] Even after a successful Phase III study, which may take another 5 years, the investigators will likely face additional challenges to bringing NES/T to market, such as finding commercial investors and manufacturers.

[61] Realistically, long-term trials in sufficient numbers of couples will require years before a product could reach the market. Regulatory agencies will need to provide guidance on what is required for approval of this new class of drugs. Additionally, pharmaceutical investment will be critical to achieve this goal. … Hormonal male contraceptive methods have proven effective in clinical trials. Regulatory approval of a new contraceptive drug for women usually requires 20 000 cycles of safety and contraceptive efficacy evaluation for at least 1 year of use. Long-term safety of a male method will need to be demonstrated before a drug would pass regulatory approval.

[62] “The results have been much better than we expected, and we’re very excited,” said Diana Blithe, Ph.D., chief of NICHD’s Contraceptive Development Program, about a study of an experimental male contraceptive gel called NES/T. “The efficacy rate appears better than ‘the pill’ and, so far, seems on par with long-acting reversible contraceptives for women,” she added.

[63] [Personal communication with researchers]

Also: Inverse June 2022 “Blithe thinks it could be another 10 years before NES/T comes to market — if it gets picked up. Best-case scenario and with serious financial commitment from a commercial partner, she says it could hit shelves by 2030, which is a ways off. Still, Blithe is more optimistic now than years ago about NES/T’s success.”

[64] Male hormonal contraceptives, like their female counterparts, are likely to be associated with some

side effects, despite progress toward reducing hormone dosages and experimenting with various

adjunct progestins. Since these prototype products are novel, it is unclear what side effects will be

acceptable for uptake by users and for approval by regulatory agencies such as the US Food and

Drug Agency and the European Medicines Agency.

[65] The dosages of T and Nes were based on previous dose-finding studies (Ilani, et al., 2012; Mahabadi, et al., 2009); the dosage of testosterone in this study was reduced to minimize the likelihood of androgenic acne seen in some men in the previous studies.

[66] The NES/T phase 1 clinical trial reported acne and weight gain as two common side effects.

[67] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533104/

[68] We observed similar frequencies of AEs reported by users of male contraceptives compared with those reported by female users.

[69] If more male contraceptive methods were available, would men use them, and would their female partners trust them to do so? Despite the paucity of choices, male-directed methods comprise approximately 16% of contraception worldwide (12). Multinational survey data suggest most men welcome the development of male methods, with 44–83% of men stating they would use them if available (13, 14).

[70] Fifty percent of subjects were either satisfied or very satisfied with the T-gel-based contraceptive regimen

[71]  Over 80% of subjects reported overall satisfaction with the study gel as a potential method of contraception  

[72]Tests of an injectable hormonal contraceptive for men:  See table 3, Final Visit (FV) satisfied/very satisfied is 80.1%

[73] Tests of an injectable hormonal contraceptive for men: See Fig 4, percentage of men rating the contraceptive excellent or good= 61%  

[74] "Overall, 56% (44/79) of men were satisfied or extremely satisfied with this gel-based method of contraception

[75] Discussion of female methods has always occurred within a shared understanding that unsought pregnancy can harm and even kill women. In the approval of the first COC, regulators considered the risks of abortion and childbirth as factors in their approval decision for the contraceptive.24 Additionally, psychological harms can be accounted for and used in risk determination. For example, while 5.4% of female users report mood changes, including depression, as an AE of their hormonal contraception (table 1), that is still lower than the 20%–22% of women who may experience maternal or postpartum depression.25 The risk of the contraceptive can thus be deemed less severe than the risk that would exist if the contraceptive were not approved.

[76] The same risk analysis that is applied to women cannot be extended to men, who cannot physically get pregnant; however, a framework for evaluating the risks and benefits of male partners is an approaching ethical dilemma that regulators must contend with. Male contraceptives are often evaluated at an individual level, which does not account for benefits seen at the family level.

 Calculation of potential risk/benefit of a male contraceptive drug is challenging because men do not face medical risks associated with pregnancy and childbirth; any systemic product for men must have a strong safety profile. However, consideration of a shared risk model of the benefits of pregnancy prevention from a biologic and psychosocial context for both partners is important (37). The goal of identifying additional health benefits for male methods is especially attractive.

One survey by MCI: Men are twice as likely to prefer a non-hormonal method (80%) to a hormonal method (38%)

[77] In contrast to hormonal male contraception, where the mechanism of action is to stop sperm production through feedback inhibition of the hypothalamic–pituitary axis, the goal of nonhormonal contraceptives is to avoid the hypothalamic–pituitary axis and thereby potentially avoid side effects associated with hormones. Nonhormonal male contraceptive development is largely still in the preclinical phase and involves targeting proteins that impact either sperm production or sperm function

[78] See sections on nonhormonals and mechanical

https://www.sciencedirect.com/science/article/pii/S0960894X21002316#b0135

https://www.sciencedirect.com/science/article/pii/S0015028221002521#sec5

[79] ADAM http://www.contraline.com/product/

RISUG https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017607/ 

Vasalgel Intravas injection of Vasalgel in sexually mature adult male rhesus monkeys was effective in preventing conception in a free-living, group environment. Complications were few and similar to those associated with traditional vasectomy

[80] E.g. RISUG, ADAM, YCT529

Although some nonhormonal inhibitors and natural products have been evaluated in humans, nonhormonal male contraceptives are in early stages of development. In addition to protein targets and small molecule inhibitors described above, active research is ongoing for nonhormonal contraceptive target discovery and validation.

https://www.goodrx.com/health-topic/mens-health/male-birth-control

https://www.malecontraceptive.org/nhrmc-database.html